The present invention, in some embodiments thereof, relates to an optical detection system for liquid samples, and, more particularly, but not exclusively, to a surface plasmon resonance (SPR) system for biological assays in well plates.
Optical detection systems can be useful for detecting and measuring various target molecules, including biological analytes, or small molecules such as drugs, in a fluid sample of very small volume, as well as for studying the reaction dynamics of such target molecules with ligand molecules that they bind to. As used herein, the target molecule will be referred to as an analyte. Typically, in such a system, the fluid sample is in contact with an active surface that is coated with a ligand that binds to the analyte of interest, creating a thin layer on the surface if the analyte is present, with the rate of increase of thickness of the layer depending on the concentration of the analyte in the sample, as well as on reaction constants between the analyte and the ligand, and the surface density of the ligand. The thickness of the layer, or an effective thickness if the layer is not uniform, can be measured with great sensitivity by reflecting light from the back of the surface, and measuring the reflectance as a function of angle of incidence for a given wavelength, and/or the reflectance as a function of wavelength for a given angle of incidence. In surface plasmon resonance (SPR) detection systems, the surface is an SPR surface, coated with a thin film of a metal, such as gold, that exhibits SPR, in which the reflectance has a narrow dip near a particular angle of incidence, due to surface plasmons that are generated in the thin film of metal at that angle of incidence. The angle of incidence of maximum absorption depends sensitively on the thickness of the layer of analyte on the surface. Other optical detection methods, which can be used in such an optical detection system, include ellipsometry, total internal reflection, Brewster angle measurements, thin film interferometry, and spectroscopy from nanoparticles and from nanostructured optical gratings.
Jiri Homola, “Surface Plasmon Resonance Sensors for Detection of Chemical and Biological Species,” Chem. Rev. 108, 462-493 (2008) provides a review of the literature on SPR sensors and their uses. Rebecca L. Rich and David Myszka, “Survey of the year 2005 commercial optical biosensor literature,” Journal of Molecular Recognition 19, 478-534 (2006), reviews some of the applications of optical detection systems for studying the reaction kinetics of biomolecules.
U.S. Pat. No. 7,582,487 to Malmqvist et al describes an SPR system that uses microfluidic channels, with individually controlled valves, as well as a system using laminar flow techniques, to position a fluid flow over a discrete sensing area of a sensing surface. One sensing area can be sensitized by exposure to an analyte-specific ligand, while one or more non-sensitized areas can be used as a reference area, or sensitized with a control ligand. Such a microfluidic SPR system with active sensing areas and a reference area is also described, for example, in Charles E. H. Berger, Tom A. M. Beumer, Rob P. H. Kooyman, and Jan Greve, “Surface Plasmon Resonance Multisensing,” Anal. Chem. 70, 703-706 (1998), and a microfluidic SPR system is also described in U.S. Pat. No. 5,313,264 to Ivarsson.
WO98/32002 to Jorgenson et al describes an SPR-based fiber optic sensor in which a layer of an SPR supporting metal is deposited around an exposed area of a fiber optic core. A sample-drawing device such as a pipette temporarily receives the sensor for use during a sampling or testing procedure.
US2004/0186359 to Beaudoin et al describes an in vivo SPR probe surface with two regions. One region has an immobilized binding member on it that binds specifically to a marker being monitored, and the other region does not. Light from the two regions can be compared, in order to determine the presence or absence of the marker.
U.S. Pat. No. 6,480,282 to Chinowsky et al describes an SPR sensor, in which at least a portion of the inside surface of a capillary tube is an SPR surface, and samples for analysis are introduced into the capillary tube.
US2010/0103421 to Johansen et al describes a transparent wall of a cavity with a concave inner surface provided with a layer of conductive material capable of supporting SPR. There is a flow structure with one or more channels, through which a sample can flow in contact with the SPR surface, and SPR measurements are made.
U.S. Pat. No. 6,139,797 to Suzuki et al describes an immunoassay apparatus with optical fibers, each with an end serving as an SPR sensor. The end portion of the apparatus, with the SPR sensors, is disposable. Multiple fibers with different SPR sensors can be used, which can serve as positive or negative controls to distinguish specific from non-specific binding.
Japanese published Patent application JP9257806 to Uchiyama et al describes an SPR sensor apparatus, in which a disposable hollow needle is used to suck up a sample solution, and an SPR metal film is vapor-deposited on the light reflecting face of a prism at the needle.
Methods of chemically treating SPR surfaces, so that an analyte-specific ligand can be immobilized on them, are described, for example, in: U.S. Pat. No. 5,436,161 to Bergström et al; Stefan Lofas and Bo Johnsson, “A Novel Hydrogel Matrix on Gold Surfaces in Surface Plasmon Resonance Sensors for Fast and Efficient Covalent Mobilization of Ligands,” J. Chem. Soc., Chem. Commun. (1990), 1526-1528; Stefan Lofas et al, “Methods for site controlled coupling to carboxymethyldextran surfaces in surface plasmon resonance sensors,” Biosensors & Bioelectronics 10 (1995), 813-822; and in published PCT application WO 2007/049269, “Binding Layer and Methods for its Preparation and Uses Thereof,” assigned to Bio-Rad Haifa, Ltd., and with Shay Nimri as the inventor, with the same assignee and one of the same inventors as the present application.
Bio-layer interferometry (BLI), another optical detection technique, is described on the website of Forte-Bio, wwwdotfortebiodotcom/bli_technologydothtml, downloaded on Jan. 19, 2012.
The EPIC® system, an optical sensor system based on a refractive waveguide grating, is described on the website of Corning Life Sciences, at wwwdotcorningdotcom/lifesciences/epic/en/products/epic_systemdotaspx, downloaded on Mar. 1, 2012. Another optical detection system based on an optical grating, the BIND® system, is described on the website of SRU Biosystems, at wwwdotsrubiosystemsdotcom/technology/indexdothtml, downloaded on Mar. 1, 2012.
Additional background art includes EP1054250 to Taguchi et al, U.S. Pat. No. 7,394,547 to Tan et al, WO2010/077605 to Xiao et al, U.S. Pat. No. 4,240,751 to Linnecke et al, U.S. Pat. No. 5,858,799 to Yee et al, and U.S. Pat. No. 7,271,885 to Schermer.